The broad long term objectives of this proposal involve trying to determine if acamprosate is an agonist at group-I metabotropic glutamate receptors (mG1uRs). The interaction of acamprosate at these receptors may explain acamprosate's neuroprotection against ethanol withdrawal. In a fully characterized binding paradigm with the use of [3H]glutamate, a saturating concentration of sodium acamprosate will be used to compete with specific antagonists at group-I mG1uRs. These same antagonists will be used in conjunction with acamprosate and trans-AM (a nonselective group-I and group-II agonist) to determine the effects of these ligands at group-I mGluRs during ethanol withdrawal in male and female organotypic hippocampal slice cultures. The use of staurosporine (a PKC inhibitor) in these functional assays will determine if acamprosate's neuroprotection during ethanol withdrawal relies upon a functional interplay between group-I mGluRs and NMDARs. Finally, the use of ethanol naive cultures will possibly reveal changes in group-I mGluRs during ethanol withdrawal. The health relatedness of this proposal includes determining a possible component of acamprosate's mechanism of action, sexual differences in ethanol withdrawal, and the prospect of group-I mG1uRs as a novel target in treating alcoholism.